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Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words \"breast\", \"cancer\", \"trastuzumab\" and \"pregnancy\". This study was performed in accordance with the PRISMA guidelines. A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

Human epidermal growth factor receptor 2 (HER2) overexpression emerges as an attractive therapeutic target in gynecological malignancies. Recently, Trastuzumab-Deruxtecan (T-DXd) has shown substantial efficacy in HER2 overexpressing carcinomas, most prominently in ovarian, endometrial and cervical patients. We have examined the efficacy of T-DXd in patients with metastatic endometrial, ovarian and cervical malignancies that were treated in the Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens. Methods Patients with gynecological malignancies with HER2 expression 2 + /3 + as assessed by immunohistochemistry (IHC) that were treated with T-DXd were retrospectively identified. Patients received T-DXd intravenously at a dose of 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Results In total, 10 patients treated with T-DXd for recurrent/metastatic disease were identified. Regarding histology, there were 5 patients with uterine neoplasms (serous carcinoma ( n  = 3), uterine carcinosarcoma ( n  = 1), uterine leiomyosarcoma ( n  = 1)), 1 patient with squamous cervical carcinoma and 4 patients with ovarian cancer (ovarian carcinosarcoma (n  = 2), high-grade serous carcinoma ( n  = 1) and mucinous ovarian carcinoma ( n  = 1)). Median age was 65.4 years (25th-75th percentile, 58.1–75.2 years). 5 patients had HER2 expression 3 + by IHC and 5 patients had HER2 expression 2 + . Median number of previous lines of therapy was 4 (range 2–6), 2 patients with uterine serous carcinoma were pretreated with trastuzumab and 4 patients had already received immunotherapy. In the entire cohort median progression-free survival (PFS) was 5.4 months (95%CI 0.8–9.8 months). Regarding responses, 5 patients had partial response (including 2 patients that were pretreated with trastuzumab), 1 patient had stable disease at 12 weeks and 4 patients had disease progression at initial assessment. All patients but one that derived clinical benefit had HER2 3 + expression. Discussion In the real-world setting, T-DXd showed activity in a cohort of heavily pre-treated patients with HER2-expressing gynecological malignancies.

Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 ( NRG1 ) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. Conclusions BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.

One of the most common adverse effects of cancer and its therapeutic strategies is sarcopenia, a condition which is characterised by excess muscle wasting and muscle strength loss due to the disrupted muscle homeostasis. Moreover, cancer-related sarcopenia may be combined with the increased deposition of fat mass, a syndrome called cancer-associated sarcopenic obesity. Both clinical conditions have significant clinical importance and can predict disease progression and survival. A growing body of evidence supports the claim that physical exercise is a safe and effective complementary therapy for oncology patients which can limit the cancer- and its treatment-related muscle catabolism and promote the maintenance of muscle mass. Moreover, even after the onset of sarcopenia, exercise interventions can counterbalance the muscle mass loss and improve the clinical appearance and quality of life of cancer patients. The aim of this narrative review was to describe the various pathophysiological mechanisms, such as protein synthesis, mitochondrial function, inflammatory response, and the hypothalamic–pituitary–adrenal axis, which are regulated by exercise and contribute to the management of sarcopenia and sarcopenic obesity. Moreover, myokines, factors produced by and released from exercising muscles, are being discussed as they appear to play an important role in mediating the beneficial effects of exercise against sarcopenia.

Novel chemotherapeutic agents have marked a new era in oncology during the past decade, prolonging significantly the overall survival of breast cancer patients. Nevertheless, contemporary antineoplastic treatments can frequently cause adverse cardiovascular side effects. Common manifestations of chemotherapy-induced cardiotoxicity include cardiomyopathy, ischemia, conduction disturbances, hypertension and thromboembolic events, while the type of the treatment regimen administered crucially determines clinical outcome. The aim of this literature review is to analyze the incidence and the underlying mechanisms of cardiovascular toxicity caused by agents approved for breast cancer, as well as to describe ways of monitoring and treating the cardiotoxic effects in breast cancer patients. Moreover, our work intends to provide an easy-to-grasp synopsis of recent and clinically meaningful advances in the field.

Background/Objectives: Persistent infection with high-risk (HR) HPV genotypes is the main risk factor for the development of cervical cancer. The present analysis provides recent trends on HR-HPV infection rates and the distribution of HR-HPV genotypes among 3500 Greek women between 2021 and 2023. Methods: The detection of HR-HPVs and the specific identification of HPV16 and HPV18 were conducted using the Roche Cobas 4800 HPV assay. The genotyping of 12 other HR-HPV genotypes was performed through the Nested Multiplex PCR methodology (NMPCR). Results: The overall infection rate was 8.8% with the most prevalent HR-HPV genotype being HPV16 followed by HPV31, HPV66, HPV56, HPV51, HPV58, HPV45, HPV18, HPV68, HPV59, HPV52, HPV35, HPV39, and HPV33. Among HR-HPV-positive cases the prevalence of single, double, triple, and quadruple infections was 73.9%, 19.9%, 5.5%, and 0.7%, respectively. Age-specific analysis showed that the HR-HPV infection rate was higher in the age group of 31–35 years (25.5%) and it was estimated that multiple infections occur more often in younger women. Notably, the distribution of HR-HPV genotypes varies among different age groups. It is proposed that HPV16, HPV31, HPV56, and HPV66 may show an increased possibility of establishing long-term infections in Greek women over 36 years old. Conclusions: The high rates of specific HR-HPVs which are not included in the prophylactic vaccines underlines the significance of constant surveillance of circulating HPVs in the Greek population.

Landmark studies have established trastuzumab in the treatment of HER2-positive breast cancer. The present systematic review and meta-analysis aims to synthesize all available data, so as to evaluate the safety of trastuzumab during pregnancy. This study was performed in accordance with the PRISMA guidelines. All studies that examined the safety of trastuzumab administered during pregnancy, regardless of sample size, were considered eligible. Overall, 17 studies (18 pregnancies; 19 newborns) were included. In 55.6 % of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration was 14.8 weeks. Occurrence of oligohydramnios/anhydramnios (O/A) was the most common (61.1 %) adverse event. 73.3 % of pregnancies exposed to trastuzumab during the second/third trimester were complicated with O/A; the respective rate of pregnancies exposed to trastuzumab exclusively during the first trimester was 0 % ( P  = 0.043). The mean GA at delivery was 33.8 weeks, and the mean weight of babies at delivery was 2,261 gr. In 52.6 % of cases, a healthy neonate was born. At the long-term evaluation, all children without problems at birth were healthy with a median follow-up of 9 months, while four out of nine children facing troubles at birth were dead within an interval ranging between birth and 5.25 months. All children exposed to trastuzumab in utero exclusively in the first trimester were completely healthy at birth. Trastuzumab should not be administered during pregnancy. However, for women who become accidentally pregnant during trastuzumab administration and wish to continue pregnancy, trastuzumab should be stopped and pregnancy could be allowed to continue.

Background: HER2-positive breast cancer patients receiving chemotherapy and targeted therapy (including anthracyclines and trastuzumab) face an elevated risk of cardiotoxicity, which can lead to long-term cardiovascular complications. Identifying predictive biomarkers is essential for early intervention. Circulating microRNAs (miRNAs), known regulators of gene expression and cardiovascular function, have emerged as potential indicators of cardiotoxicity. This study aims to evaluate the differential expression of circulating miRNAs in HER2-positive breast cancer patients undergoing chemotherapy and to assess their prognostic ability for therapy-induced cardiotoxicity using machine learning models. Methods: Forty-seven patients were assessed for cardiac toxicity at baseline and every 3 months, up to 15 months. Blood samples were collected at baseline. MiRNA expression profiling for 84 microRNAs was performed using the miRCURY LNA miRNA PCR Panel. Differential expression was calculated via the 2−∆∆Ct method. The five most upregulated and five most downregulated miRNAs were further assessed using univariate logistic regression and receiver operating characteristic (ROC) analysis. Five machine learning models (Decision Tree, Random Forest (RF), Support Vector Machine (SVM), Gradient Boosting Machine (GBM), k-Nearest Neighbors (KNN)) were developed to classify cardiotoxicity based on miRNA expression. Results: Forty-five miRNAs showed significant differential expression between cardiac toxic and non-toxic groups. ROC analysis identified hsa-miR-155-5p (AUC 0.76, p = 0.006) and hsa-miR-124-3p (AUC 0.75, p = 0.007) as the strongest predictors. kNN, SVM, and RF models demonstrated high prognostic accuracy. The decision tree model identified hsa-miR-17-5p and hsa-miR-185-5p as key classifiers. SVM and RF highlighted additional miRNAs associated with cardiotoxicity (SVM: hsa-miR-143-3p, hsa-miR-133b, hsa-miR-145-5p, hsa-miR-185-5p, hsa-miR-199a-5p, RF: hsa-miR-185-5p, hsa-miR-145-5p, hsa-miR-17-5p, hsa-miR-144-3p, and hsa-miR-133a-3p). Performance metrics revealed that SVM, kNN, and RF models outperformed the decision tree in overall prognostic accuracy. Pathway enrichment analysis of top-ranked miRNAs demonstrated significant involvement in apoptosis, p53, MAPK, and focal adhesion pathways, all known to be implicated in chemotherapy-induced cardiac stress and remodeling. Conclusions: Circulating miRNAs show promise as biomarkers for predicting cardiotoxicity in breast cancer patients. Machine learning approaches may enhance miRNA-based risk stratification, enabling personalized monitoring and early cardioprotective interventions.

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Plasma cell‐free DNA (cfDNA) analysis to track estrogen receptor 1 (ESR1) mutations is highly beneficial for the identification of tumor molecular dynamics and the improvement of personalized treatments for patients with metastatic breast cancer (MBC). Plasma‐cfDNA is, up to now, the most frequent liquid biopsy analyte used to evaluate ESR1 mutational status. Circulating tumor cell (CTC) enumeration and molecular characterization analysis provides important clinical information in patients with MBC. In this study, we investigated whether analysis of CTCs and circulating tumor DNA (ctDNA) provide similar or complementary information for the analysis of ESR1 mutations. We analyzed both plasma‐cfDNA (n = 90) and paired CTC‐derived genomic DNA (gDNA; n = 42) from 90 MBC patients for seven ESR1 mutations. Eight out of 90 (8.9%) plasma‐cfDNA samples tested using the ddPLEX Mutation Detection Assay (Bio‐Rad, Hercules, CA, USA), were found positive for one ESR1 mutation, whereas 11/42 (26.2%) CTC‐derived gDNA samples were found positive for at least one ESR1 mutation. Direct comparison of paired samples (n = 42) revealed that the ESR1 mutation rate was higher in CTC‐derived gDNA (11/42, 26.2%) than in plasma‐cfDNA (6/42, 14.3%) samples. Our results, using this highly sensitive ddPLEX assay, reveal a higher percentage of mutations in CTC‐derived gDNAs than in paired ctDNA in patients with MBC. CTC‐derived gDNA analysis should be further evaluated as an important and complementary tool to ctDNA for identifying patients with ESR1 mutations and for guiding individualized therapy. Analysis of ESR1 mutations in plasma cell‐free DNA (cfDNA) is highly important for the selection of treatment in patients with breast cancer. Using multiplex‐ddPCR and identical blood draws, we investigated whether circulating tumor cells (CTCs) and cfDNA provide similar or complementary information for ESR1 mutations. Our results indicate a higher detection rate for ESR1 mutations in CTCs than in paired cfDNA.